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PDBsum entry 4upt
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Oxidoreductase
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PDB id
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4upt
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Structure of bovine endothelial nitric oxide synthase heme domain in complex with n'-[4-[[(2s,4r)-4-[3-[(c-thiophen-2-ylcarbonimidoyl) amino]phenoxy]pyrrolidin-2-yl]methoxy]phenyl]thiophene-2- carboximidamide
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Structure:
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Nitric oxide synthase, endothelial. Chain: a, b. Fragment: heme domain, residues 40-482. Synonym: constitutive nos, cnos, ec-nos, endothelial nos, enos, nos type iii, nosiii, endothelial nitric oxide synthase. Engineered: yes
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Source:
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Bos taurus. Cattle. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.20Å
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R-factor:
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0.185
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R-free:
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0.236
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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Q.Jing
et al.
(2014).
Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase.
Bioorg Med Chem Lett,
24,
4504-4510.
PubMed id:
DOI:
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Date:
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17-Jun-14
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Release date:
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20-Aug-14
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PROCHECK
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Headers
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References
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P29473
(NOS3_BOVIN) -
Nitric oxide synthase 3 from Bos taurus
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Seq:
Struc:
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1205 a.a.
405 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.1.14.13.39
- nitric-oxide synthase (NADPH).
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Reaction:
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2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
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2
×
L-arginine
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+
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3
×
NADPH
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+
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4
×
O2
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+
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H(+)
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=
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2
×
L-citrulline
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+
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2
×
nitric oxide
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+
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3
×
NADP(+)
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+
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4
×
H2O
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
24:4504-4510
(2014)
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PubMed id:
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Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase.
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Q.Jing,
H.Li,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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To develop potent and selective nNOS inhibitors, a new series of double-headed
molecules with chiral linkers that derive from natural amino acid derivatives
have been designed and synthesized. The new structures integrate a
thiophenecarboximidamide head with two types of chiral linkers, presenting easy
synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of
14.7nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS
and iNOS, respectively. Crystal structures show that the additional binding
between the aminomethyl moiety of 9b and propionate A on the heme and
tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high
selectivity. This work demonstrates the advantage of integrating known
structures into structure optimization, and it should be possible to more
readily develop compounds that incorporate bioavailability with these advanced
features. Moreover, this integrative strategy is a general approach in new drug
discovery.
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Links
